Tuning Stereoselection in Tethered Biginelli Condensations. Synthesis of cis- or trans-1-Oxo- and 1-Iminohexahydropyrrolo[1,2-c]pyrimidines

Abstract

Stereoselection in tethered Biginelli condensations can be tuned to give either the cis or trans stereoisomer of 1-oxohexahydropyrrolo[1,2-c]pyrimidine and 1-iminohexahydropyrrolo[1,2-c]pyrimidine products (see eq 1). With substrates having urea and N-sulfonylguanidine functionality (Schemes 2 and 4), cis stereoselection (4-7:1) is observed when the condensation is accomplished under Knoevenagel conditions, while trans stereoselection (4-20:1) is observed when the condensation is carried out in the presence of polyphosphate ester (PPE). Under both conditions, steroselectivity is highest in the N-sulfonylguanidine series. With substrates bearing a basic guanidine unit, the trans product is formed exclusively under Knoevenagel conditions (Scheme 3).

The tethered Biginelli condensation in natural product synthesis

“…These workers showed that higher yields, and in some cases higher stereoselectivities, were realized in polar, protic solvents such as methanol or trifluoroethanol. 24 Renhowe also found that the reaction gave higher yields and improved stereoselectivity in the presence of morpholinium acetate (pK a = 8.3) than with piperidinium acetate (pK a = 11.1). 25 Intermediates such as 14 are complex mixtures that contain traces of the acyclic ureido aldehyde, the depicted 2-hydroxypyrrolidine isomer, as well as higher molecular weight oligomers.…”

Similarity and Competition between Biginelli and Hantzsch Reactions: an Opportunity for Modern Medicinal Chemistry

“…[14,48] The reaction has also been realized in an asymmetric manner. [49][50][51][52] Total synthesis of natural polycyclic guanidine alkaloids has been accessed by the Biginelli reaction by simply replacing urea with a suitable guanidinium component. [53][54][55] The Biginelli reaction was ultimately exploited in material chemistry as direct, convergent and easy reaction for the development of functional materials such as polymers, dyes or adhesives.…”

Synthesis of Novel Functionalized Derivatives of 5-Nitro-3,4-dihydropyrimidin-2(1H)-one by the Cyclocondensation of 1-Chlorobenzyl Isocyanates with N,S- and N,N-Nitroketeneacetals

“…5 Modified ap-proaches to DHPM synthesis, for example those proposed by Atwald and Shutalev, 6 have also been reported. The condensed DHPM nucleus of the alkaloids batzelladines B and D was constructed using the condensation between acetoacetic ester and a complex derivative of N-a-hydroxyalkyl urea; 7 in a more recent example, vinyl carbodiimides were cycloadded to chiral cyclic imines. 8 To obtain partially hydrogenated derivatives of pyrrolo [1,2c]pyrimidine, constituting the heterocyclic system of saxitoxin, Kishi suggested the condensation of 2-carbethoxymethylidenepyrrolidine with isocyanic acid and acetaldehyde.…”